The effects of acute hyponatraemia on bone turnover in patients with subarachnoid haemorrhage: A preliminary report.

CONTEXT: Animal data and cross-sectional human studies have established that chronic hyponatraemia predisposes to osteoporosis; the effects of acute hyponatraemia on bone turnover have not been determined. Our objective was to test the hypothesis that acute hyponatraemia leads to dynamic effects on bone turnover. DESIGN: A prospective observational pilot study. METHODS: Bone turnover markers [C-terminal crosslinking telopeptide of type 1 collagen (CTX-1), N-propeptide of type 1 collagen (P1NP) and osteocalcin] were measured prospectively over one week in 22 eunatraemic patients with subarachnoid haemorrhage. Patients treated with glucocorticoids were excluded. RESULTS: Eight patients developed acute hyponatraemia, median nadir plasma sodium concentration 131 mmol/L (IQR 128-132), and 14 remained eunatraemic, nadir plasma sodium concentration 136 mmol/L (IQR 133-137). Significant main effects of hyponatraemia were found for P1NP (p = .02) and P1NP:CTX-1 ratio (p = .02), both fell in patients with acute hyponatraemia, with significant interaction between hyponatraemia and time from baseline for P1NP (p = .02). Significant main effects of time from baseline (p < .001) but not hyponatraemia (p = .07) were found for osteocalcin. For CTX-1, significant main effects of time from baseline (p = .001) but not hyponatraemia (p = .65) were found. There was a positive correlation between change in P1NP:CTX-1 ratio and nadir plasma sodium concentration, r = +.43, p = .04. Median serum cortisol (measured on days 1, 3 and 7) was higher in the hyponatraemia group than in those who remained eunatraemic, 545 nmol/L (IQR 373-778) versus 444 nmol/L (IQR 379-542) p = .03. CONCLUSION: These data suggest that acute mild hyponatraemia is associated with a reduction in bone formation activity.

Active management of hyponatraemia and mortality in older hospitalised patients compared with younger patients: results of a prospective cohort study.

INTRODUCTION: Hyponatraemia is associated with increased morbidity and mortality; the aetiology and outcomes of hyponatraemia in older patients have not been defined in prospective studies. METHODS: A single-centre 9-month prospective observational study in which clinical outcomes in hospitalised patients ≥ 65 years (older patients with hyponatraemia (OP-HN)) and those <65 years (young patients with hyponatraemia (YP-HN)) with hyponatraemia were analysed, and compared with eunatraemic controls (older patients with normonatraemia (OP-NN) and young patients with normonatraemia (YP-NN)). RESULTS: In total, 1,321 episodes of hyponatraemia in 1,086 patients were included; 437 YP-HN, median age 54 years (IQR 44,60) and 884 OP-HN, median age 77 years (IQR 71,82). A total of 1,120 consecutive eunatraemic control patients were simultaneously recruited; 690 OP-NN, median age 77 years (IQR 71,83) and 430 YP-NN, median age 52 years (IQR 41,58). Euvolaemic hyponatraemia was the commonest cause of hyponatraemia in both age groups (48% in YP-HN and 46% in OP-HN). Sixty-two percent of OP-HN received hyponatraemia-directed treatment within the initial 48 h, compared with 55% of YP-HN, P = 0.01. Despite the greater treatment rates in OP-HN, younger patients were 24% more likely to be discharged with normal plasma sodium concentration (pNa) compared with older patients, relative risk (RR) 1.24 (95% confidence interval (CI) 1.12-1.37), P < 0.001.Using OP-NN as the reference group, the RR of in-hospital death in OP-HN was 2.15 (95% CI 1.3-3.56), P = 0.002. Using YP-NN as the reference group, the RR of in-hospital death in YP-HN was 4.34 (95% CI 1.98-9.56), P < 0.001. CONCLUSION: Despite greater rates of HN-targeted treatment, the risk of in-hospital death is increased in older hyponatraemic patients compared with older eunatraemic controls. The impact of hyponatraemia on mortality is even greater in younger patients.

Oxycodone in Palliative Care-Art and Empathy Still Have a Place.

A 47-year-old woman who was receiving palliative care for metastatic breast cancer, which included oxycodone, was found dead in bed. The femoral blood level of oxycodone at autopsy was 1200 µg/L, which is a value within the lethal range. Could the cause of death be attributed to misadventure or suicide? Would the coroner consider a recommendation of therapeutic drug monitoring in palliative care which could have a serious negative impact on pain relief practice? A narrative verdict was the outcome linking the primary cause of death with the drug cocktail found at autopsy.

The complexity of PSA interpretation in clinical practice.

Prostate specific antigen (PSA) is central to the diagnosis of prostate cancer. Laboratories quote cut-off reference ranges for PSA but values within these boundaries do not equate with an absence of cancer nor do levels above the range equate with its presence. Convention places the cut-off value at 4 µg/L when calibrated to the Hybritech immunoassay technology and 3.0 or 3.1 µg/L if the PSA methods are calibrated to the WHO IRP 96/670 standard. The prevalence of prostate cancer in screened normal men over 55 years of age with PSA values less than 4 µg/L (Hybritech method) is 10.1% at a PSA of 0.6-1.0 µg/L. About 12.5% of these will be high grade. Two major randomised trials reported on PSA screening. The European trial (ERSPC) reported a risk reduction for prostate cancer death of 21% in the screened group but the US PLCO trial found no benefit. PSA results depend on calibration and there is a 22% difference between the older Hybritech and newer WHO standardisation. Biological variation in PSA is a geometric mean of 7.3%. External quality assessment schemes show wide variation in the performance of PSA analysis. Neither the American College of Physicians nor the UK National Health Service recommends screening except when there is increased risk through family history or ethnicity. Laboratories should detail their method calibration in each report and clinicians should be alerted to the potential misclassification of patients through PSA variation.

Hospital Outcomes in Patients Hospitalized for COVID-19 Pneumonia: The Effect of SARS-CoV-2 Vaccination and Vitamin D Status.

SARS-CoV-2 vaccination promises to improve outcomes for patients with COVID-19 pneumonia (most notably those with advanced age and at high risk for severe disease). Here, we examine serum 25-Hydroxyvitamin D (25(OH)D) status and outcomes in both old (>70 years) and young vaccinated (n = 80) and unvaccinated (n = 91) subjects, who were hospitalized due to COVID-19 pneumonia in a single center (Connolly Hospital Dublin). Outcomes included ICU admission and mortality. Serum 25(OH)D levels were categorized as D30 (<30 nmol/L), D40 (30-49.99 nmol/L) and D50 (≥50 nmol/L). In multivariate analyses, D30 was independently associated with ICU admission (OR: 6.87 (95% CI: 1.13-41.85) (p = 0.036)) and mortality (OR: 24.81 (95% CI: 1.57-392.1) (p = 0.023)) in unvaccinated patients, even after adjustment for major confounders including age, sex, obesity and pre-existing diabetes mellitus. While mortality was consistently higher in all categories of patients over 70 years of age, the highest observed mortality rate of 50%, seen in patients over 70 years with a low vitamin D state (D30), appeared to be almost completely corrected by either vaccination, or having a higher vitamin D state, i.e., mortality was 14% for vaccinated patients over 70 years with D30 and 16% for unvaccinated patients over 70 years with a 25(OH)D level greater than 30 nmol/L. We observe that high mortality from COVID-19 pneumonia occurs in older patients, especially those who are unvaccinated or have a low vitamin D state. Recent vaccination or having a high vitamin D status are both associated with reduced mortality, although these effects do not fully mitigate the mortality risk associated with advanced age.

Active management of severe hyponatraemia is associated with improved mortality.

OBJECTIVE: Severe hyponatraemia (plasma sodium concentration, pNa <120 mmol/L) is reported to be associated with mortality rates as high as 50%. Although there are several international guidelines for the management of severe hyponatraemia, there are few data on the impact of treatment. DESIGN AND METHODS: We have longitudinally reviewed rates of specialist input, active management of hyponatraemia, treatment outcomes and mortality rates in patients with severe hyponatraemia (pNa <120 mmol/L) in 2005, 2010 and 2015, and compared the recent mortality rate with that of patients with pNa 120-125 mmol/L. RESULTS: Between 2005 and 2010 there was a doubling in the rate of specialist referral (32 to 68%, P = 0.003) and an increase in the use of active management of hyponatraemia in patients with pNa <120 mmol/L (63 to 88%, P = 0.02), associated with a reduction in mortality from 51 to 15% (P < 0.001). The improved rates of intervention were maintained between 2010 and 2015, but there was no further reduction in mortality. When data from all three reviews were pooled, specialist consultation in patients with pNa <120 mmol/L was associated with a 91% reduction in mortality risk, RR 0.09 (95% CI: 0.03-0.26), P < 0.001. Log-rank testing on in-hospital survival in 2015 found no significant difference between patients with pNa <120 mmol/L and pNa 120-125 mmol/L (P = 0.56). CONCLUSION: Dedicated specialist input and active management of severe hyponatraemia are associated with a reduction in mortality, to rates comparable with moderate hyponatraemia.

The diagnostic utility of late night salivary cortisol (LNSF) and cortisone (LNSE) in Cushing's syndrome.

BACKGROUND: Measurement of late night salivary cortisol (LNSF) is useful in the identification of cyclical Cushing's syndrome (CS); the usefulness of its metabolite cortisone (late night salivary cortisone, LNSE) is less well described. AIM: The aim of this study was to determine the utility of measuring LNSE in patients with confirmed CS compared with other diagnostic tests and to analyse serial LNSF measurements for evidence of variable hormonogenesis. METHODS: This was a retrospective observational study including patients with confirmed CS in whom LNSF and LNSE were measured. RESULTS: Twenty-three patients with confirmed CS were included, 21 with Cushing's disease. LNSF had a sensitivity of 92%, LNSE 87% and combined LNSF/LNSE 94% per sample. Four patients had cyclical hormonogenesis, when the definition of one trough and two peaks was applied to LNSF measurements, and a fifth patient fell just outside the criteria. Six patients had evidence of variable hormonogenesis, defined as doubling of LNSF concentration on serial measurements. Sensitivity of 24-h urinary free cortisol (UFC) was 89% per collection. Sixteen patients had simultaneous measurements of LNSF and UFC; in three patients, they provided discordant results. CONCLUSION: LNSF appears more sensitive than LNSE and UFC in the diagnosis of CS, combining LNSF and LNSE results leads to superior sensitivity. Half of our cohort had evidence of cyclical or variable hormonogenesis. Fluctuations in LNSF did not always correlate with changes in UFC concentration, emphasising the importance of performing more than one screening test, particularly if pretest clinical suspicion is high.

Fluid Restriction Therapy for Chronic SIAD; Results of a Prospective Randomized Controlled Trial.

CONTEXT: Fluid restriction (FR) is the recommended first-line treatment for syndrome of inappropriate antidiuresis (SIAD), despite the lack of prospective data to support its efficacy. DESIGN: A prospective nonblinded randomized controlled trial of FR versus no treatment in chronic SIAD. INTERVENTIONS AND OUTCOME: A total of 46 patients with chronic asymptomatic SIAD were randomized to either FR (1 liter/day) or no specific hyponatremia treatment (NoTx) for 1 month. The primary endpoints were change in plasma sodium concentration (pNa) at days 4 and 30. RESULTS: Median baseline pNa was similar in the 2 groups [127 mmol/L (interquartile range [IQR] 126-129) FR and 128 mmol/L (IQR 126-129) NoTx, P = 0.36]. PNa rose by 3 mmol/L (IQR 2-4) after 3 days FR, compared with 1 mmol/L (IQR 0-3) NoTx, P = 0.005. There was minimal additional rise in pNa by day 30; median pNa increased from baseline by 4 mmol/L (IQR 2-6) in FR, compared with 1 mmol/L (IQR 0-1) NoTx, P = 0.04. After 3 days, 17% of FR had a rise in pNa of ≥5 mmol/L, compared with 4% NoTx, RR 4.0 (95% CI 0.66-25.69), P = 0.35. After 3 days, 61% of FR corrected pNa to ≥130 mmol/L, compared with 39% of NoTx, RR 1.56 (95% CI 0.87-2.94), P = 0.24. CONCLUSION: FR induces a modest early rise in pNa in patients with chronic SIAD, with minimal additional rise thereafter, and it is well-tolerated. More than one-third of patients fail to reach a pNa ≥130 mmol/L after 3 days of FR, emphasizing the clinical need for additional therapies for SIAD in some patients.

COVID-19 in adults: test menu for hospital blood science laboratories.

INTRODUCTION: Coronavirus disease 2019 (COVID-19), is a respiratory illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Clinical Blood Sciences Laboratory (CBSL) plays a key role in supporting the monitoring and management of patients with COVID-19 disease. OBJECTIVE: To provide a comprehensive CBSL testing protocol to support the medical management of SARS-CoV-2 infection. METHODS: Description of the biochemical, haematological and immunological tests that have a role in the assessment and monitoring of patients with COVID-19 infection. RESULTS: We provide a test menu for clinical laboratories to ensure the effective monitoring, management and prognostication of COVID-19 patients in hospital. CONCLUSION: Given the rapidity with which patients with COVID-19 disease can deteriorate, we recommend regular testing with vigilance paid to the rate and trajectory of change in each of these parameters.

Should serum calcitonin be routinely measured in patients presenting with thyroid nodule?

BACKGROUND: The European Thyroid Association recommends serum calcitonin measurement in thyroid nodule cases. In contrast, the American Thyroid Association is ambivalent. In this institution, thyroid nodules cases are subject to a multidisciplinary evaluation of the clinical history and examination, ultrasound and scintigraphy, CT scan and sometimes MRI scan, biochemistry and histopathology of biopsies. We report on the current use of plasma calcitonin measurements in the context of changing practice which has not included screening of all thyroid nodules. METHODS: Laboratory records were searched from the beginning of January 2010 to the end of April 2016 for all serum calcitonin measurements. RESULTS: There were 44 patients (30 females, age range 31 to 87 years with median 57.5) and 14 males, age range 20 to 85 years with median 53.4 years) who had a serum calcitonin measured. Of these 33 patients did not have a detectable serum calcitonin. There were 3 patients who had an initial elevated serum calcitonin which became undetectable over time. Over the same time period, a total of 2070 patients presented with thyroid nodules. Medullary thyroid cancer (MTC) was found in 7 cases. Thus assuming all MTC cases had calcitonin measured, MTC is 7 of 341 (2.05%) of the total thyroid cancer burden at the hospital and 7 of 2070 (0.338%) of all thyroid nodules. Our practice is not to routine screen all nodules for MTC. CONCLUSIONS: Because patients with a nodule are subjected to ultrasound scanning and biopsy, when the nodule size is greater than 5 cm or when there is a modifying ultrasound or clinical characteristic, the consensus at the multidisciplinary conference on thyroids rather than universal calcitonin screening of all nodules is the better option in our judgement.

The spectrum of expert reports on clinical biochemical toxicology and medicine from an Irish practice.

The compounds which generated an expert opinion report in the area of medical toxicology in the period 1999 to 2015 are presented from the toxicological case files of a specialist in chemical pathology and general internal medicine. There were 132 different compounds from 86 cases. Alcohol was involved in 43%, drugs of abuse in 18.6%, volatile carbon compounds in 17.4%, metals in 9.3%, and carbon monoxide in 4.6%. Many compounds appeared once. The duty of the medical expert witness to provide an objective report for the court irrespective of the payer is stated. The addition of references from peer reviewed literature to substantiate the pros and cons of each case is recommended as a standard operating procedure in completing each report.

Newspaper reports from the Coroners Court in Ireland are used to reveal the potential complexity and need for reform in forensic toxicology and medicine services.

Newspapers devote regular space to inquests in the public interest. Accuracy in determining the causes of death is important for public health. Expert opinion features prominently in press reports and is an important channel of public education. How expert are the experts and how complex are apparently simple cases? Toxicology cases involving cannabis and stroke, 'junk food' diet, unexplained sudden death, potential drug interactions, allergy during caesarean section, and ecstacy-type drugs are used to illustrate the complexities. A template for reform is suggested to reform the Coroners Laws in Ireland to recognise the complexity of forensic toxicology and medicine.

Cerebrospinal fluid protein and glucose examinations and tuberculosis:Will laboratory safety regulations force a change of practice?

Cerebrospinal fluid (CSF) protein and glucose examinations are usually performed in chemical pathology departments on autoanalysers. Tuberculosis (TB) is a group 3 biological agent under Directive 2000/54/EC of the European Parliament but in the biochemistry laboratory, no extra precautions are taken in its analysis in possible TB cases. The issue of laboratory practice and safety in the biochemical analyses of CSF specimens, when tuberculosis infection is in question is addressed in the context of ambiguity in the implementation of current national and international health and safety regulations. Additional protective measures for laboratory staff during the analysis of CSF TB samples should force a change in current laboratory practice and become a regulatory issue under ISO 15189. Annual Mantoux skin test or an interferon-γ release assay for TB should be mandatory for relevant staff. This manuscript addresses the issue of biochemistry laboratory practice and safety in the biochemical analyses of CSF specimens when tuberculosis infection is in question in the context of the ambiguity of statutory health and safety regulations.

Fault lines in forensic medical toxicology in Ireland exposed through replies of pathologists and coroners to anonymous questionnaires.

The attitudes and experiences of pathologists and coroners to the provision of biochemical forensic toxicology in the Republic of Ireland were determined using separate questionnaires to each group anonymously. Replies were received from 36/88 (41%) of pathologists and 19/71 (27%) of coroners. 37% of coroners considered that histopathologists give an adequate opinion in forensic toxicology yet 58% of pathologists reported that they did not have adequate access to expert medical interpretative toxicological opinion. For drug-drug interactions and metabolic diseases, 69% of pathologists were unhappy with the processes and 68% of coroner replies did not know if vitreous samples were used appropriately. There is a clear requirement for retraining of coroners and for the appointment of medical toxicology expertise to improve the quality of service for coroners.